PD-1, a member of the immunoglobulin (Ig) superfamily, is highly upregulated on activated lymphocytes and monocytes. PD-1 was first identified by subtraction hybridization of a T-cell hybridoma undergoing programmed cell death. PD-1 is expressed on activated CD4+ and CD8+ T cells, B cells and myeloid cells. It interacts with its two known ligands PD-L1 (B7-H1) and PD-L2 (B7-DC). PD-L1 is constitutively expressed on splenic T cells, B cells, monocytes, macrophages and dendritic cells (DCs), and its expression can be induced by activation of T lymphocytes, monocytes, macrophages and DCs. PD-L2 is expressed on non-lymphoid tissues and is upregulated on monocytes and DCs after activation.
PD-1 ligation seems to have an inhibitory effect on the immune response to viral infections; hence following infection with adenovirus, PD-1−/− mice exhibited increased proliferation of effector T-cells in the liver and enhanced virus clearance. Similar results were obtained also in a murine model of Herpes simplex virus (HSV) infection where administration of anti-PD-L1 restored HSV-1 specific responses. More recently, Barber et al. confirmed that PD-1 is upregulated on CD8+ T cells from both acute and chronic (lab-derived strains) LCMV infected mice; however, while PD-1 expression was lost on CD8+ T cells upon viral clearance, it remained upregulated on CD8 T cells from chronically-infected mice (Barber et al., 2006, Nature 439(7077): 682-687). Blocking the PD-1/PD-L1 pathway through the administration of PD-1- or PD-L1-specific antibodies into mice chronically infected with LCMV restored cytokine secretion, cytotoxic activity and the capacity of exhausted CD8+ T cells to proliferate and, to decrease viral load.
Also, PD-1-deficient mice exhibit an autoimmune phenotype. PD-1 deficiency in the C57BL/6 mice results in chronic progressive lupus-like glomerulonephritis and arthritis (Nishimura et al., 1999, Immunity 11(2): 141-151). In Balb/c mice, PD-1 deficiency leads to severe cardiomyopathy due to the presence of heart-tissue-specific self-reacting antibodies (Nishimura et al., 2001, Science 291(5502): 319-322).
Given the role of PD-1 activity in immune function, there is a need for the development of reagents, kits and methods for modulation of the PD-1-associated processes.